The panel discussed topics of interest that at first seemed unconnected, but by the end of the discussion the topics revealed a connectedness that is detailed below. The first theme centered on disparity in the cancer care landscape, and segued into cancer services such as palliative care. Big cancer data was also discussed which then led to how data are being used to evolve into the future of how cancer care will be decided upon and delivered to patients.

The Haves versus The Have Nots

According to Goodman, until the issue of looking at the “haves” versus the “have nots” as supplements to cancer care is addressed, “we will not have made progress.” This thought was exemplified by Dr. Higgins, whose clinical expertise lies in the areas of cervical and breast cancers. In one of the wealthiest states in the nation, Connecticut, where Dr. Higgins has a clinical practice, she informed that she still sees patients with stage IV cervical cancer “which really at this point should be a third-world country disease.” The disparity in income in that area of her state ranges from those who make well over $100,000 annually to the underprivileged with an income of less than $25,000. “What we see is that poverty and socio-economic class is tied to the stage of presentation and the type of disease,” she said.

Because of the disparities in care that do exist, private insurance companies such as Priority Health, a group-based insurance company located in Michigan, have a specific interest in cancer care. With the financial squeeze being placed on the shoulders of the middle class, Dr. Fox attributes some of the disparity to the healthcare exchanges and subsidies providing more economic support for the low-income population, not only with the premium subsidies but also with the cost-sharing subsidies. For instance, a plan member from the middle class could have up to $6,000 individual out of pocket expenses a year and $12,000 for a family, whereas low-income and even Medicaid patients will have much smaller cost burden.
According to Jack Mahoney from the Florida Healthcare Coalition, they are hearing from employers that new hires are falling into a higher risk profile category than new hires before the recession. They are presenting at a later stage of disease than they were in the past. “I think this is a reflection of the fact that in economic down times, people by-pass preventive care, they by-pass screenings, and then suddenly they’re in a health plan and have access to care.”

Considering the broad populations that Dr. Higgins’ sees and the diverse set of employees going back to work, the question becomes: How will healthcare reform solve this disparity problem? Different levels of plans that are going to be offered through exchanges, such as the bronze, silver, or gold plans, are not going to be as richly designed as what was seen in the past. For example, Dr. Mahoney described, the bronze plan is designed to pay 60% of a patient’s costs, “so people will think that they have coverage, and indeed they do for preventive care, and for some routine things.” But the reality is for the middle class they’re going to see a higher out of pocket if they’re in one of these bronze or silver plans, as 40% is a very large out of pocket expense, especially for someone who’s making less than $30,000 annually.
So while healthcare reform may broaden access to care, it may not amount to much with the escalating costs of care and most people being unable to afford their deductibles.

One of the things that come to mind for Dr. von Eschenbach with the disparity issue is from the point of view of outcomes. According to him, people who don’t have access to and are not familiar with the digital world, are going to be significantly disadvantaged. “[Disparity] is not simply a socio-economic issue,” he said, “It’s also a cultural issue.”

The Discussion of Palliative Care

There are a host of experiments going on around the country that are focused on how to better pay for cancer care. Traditionally, Dr. Fox explained, “we have just paid whatever has come across the claim system.” But in Priority Health’s way of thinking he said, “We need to become more focused on the outcomes that are valuable for the patients.” This would include palliative care which according to Dr. Higgins is a neglected aspect of care. As physicians, “we spend a lot of healthcare dollars in the last six months of life, and we’re doing all the talking, which is not reimbursed,” she said.

Because having the end of life discussion is a very hard thing to have, Dr. Beveridge encourages the absolute training of physicians on how to have this discussion with patients and their families. Palliative care is a very new specialty. “We don’t have the manpower to do it. It’s going to take us years to train up. We’ve actually found that it’s frequently better to have a nurse practitioner or social worker introduce the topic and say to the patient, it’s ok to talk to your doctor about this, because we as physicians are not trained to do this; we don’t do it particularly well and I think you need almost to have that intermediary to start the discussion.”
Lee Newcomer, MD, reflected on this sentiment and discussed the philosophical barrier in the United States that suggests that “Americans don’t think death is an option. We struggle with facing that and quite frankly, the whole nomenclature about the war on cancer suggests that this is a battle that we can’t give up on. We have a whole culture that says it’s wrong to stop.”

Cancer Big Data

In turning the conversation to outcomes data and personalized medicine, Dr. Goodman questioned the panel about cancer big data. Will big data provide the information needed to influence prescribing habits and eventually get the right medicines to the right patient? Dr. Kohn led this part of the discussion by describing Watson – the IBM artificial intelligence computer system that is capable of answering questions posed in natural language. A version of Watson played Jeopardy! Watson can read and understand 200 million pages of text in three seconds. And if that’s not impressive enough, Watson can read and understand whatever text-like information is made available to it.

In development with Memorial Sloan Kettering Cancer Center and Wellpoint Inc., Watson is being taught to understand the critical attributes of the history of a patient with cancer, and then search through data (such as the NCCN guidelines) and come back with suggestions for the oncologists that patients can consider as personalized, because the brain understands the full history of the patient and the difficult co-morbidities of the patient. In other words, if there’s something relevant, Watson can bring it to a practitioner’s attention.
Dr. Kohn also pointed out that “Big data isn’t just lots of data. It’s often described as the four V’s which is Volume, Velocity, Variety, and Variability. It’s unique to deal with the four of those V’s if you’re going to do anything useful with the information.”

With Lee Newcomer, mining big data at UnitedHealthcare involves the collection of data on 70 to 80 million people and placing that data in a basic research center where physicians of any type will have access after putting forward their proposal. “On the cancer basis, we’re trying to create a cancer registry that combines clinical data from state tumor registries with our claims data. What that allows us to do is basically create a longitudinal record for the patient.” In the two or three years, United intends to start profiling chemotherapy regimens. “We can tell when a patient started on a given regimen, we can tell when they’ve progressed – we do that by assuming progress when a new drug is added and the others are dropped – and we can actually calculate real world progression free survivals for a given chemotherapy regimen.” According to Newcomer, “What you are going to get out of big data are a lot of hypotheses that need to be tested. But, you’re going to get good hypotheses that help you find a better population of patients for a given treatment.”

For Dr. Beveridge, the whole concept of big data is crucially important, “but I look at it as much as an attempt to begin to change how we look at quality in the care that we render.” At McKesson, an immense amount of data can be acquired, “but the data integrity is remarkably important and as we’re putting together data in the next number of years, we really have to begin to codify how we put data in and how we talk with various electronic health records to get these data out. When we look at quality that’s based on processes, this amalgamation of data is going to allow us to get to understanding what outcomes are. Once we get there then I think we have collectively a definition of quality which I think is good for everyone.”

Moving Forward Into a Brave New World

Goodman moved the conversation towards the evolving ecosystem that is needed to transform cancer care. Dr. Fox warned to be careful about big data because “I think what big data will tell us, is what appropriate options are, or better options are for patients, but we can’t use that information in a vacuum – it really depends on what the patient wants.” Dr. von Eschenbach felt “we’re falling into a trap. The trap being that this is going to enable us to take 8 treatments down to 2 treatments.” To von Eschenbach, it’s not a matter of going from 8 treatments to 2 treatments, but of the 8 treatments, which of those is the right treatment for the right patient for the right reason. “We don’t have to restrict our options for what we can do for patients, what we do is apply those options much more rationally to the variations to the patient population that we’re dealing with.” That’s the difference, he said, between “rational” medicine and “rationed” medicine.
As for the evolving cancer care ecosystem, “We’re not there,” von Eschenbach said. “We haven’t yet emerged with regard to being able to understand how to truly do this.” He thought that the four components needed to deal with this complex solution are targeting, payload, delivery, and a monitor. “We haven’t figured out yet how to put that all together. We don’t have a way of bringing the discovery components together.”
When Goodman asked him if the research establishment is organized in a way to achieve that goal, von Eschenbach said, no. “I think that the problem has been that we were all trained to play golf – it’s been a highly egocentric, individualistic kind of culture and the game has now switched from golf to basketball, which means it’s not only about individual excellence, that’s essential – but it’s also about interoperable performance, how we can work together in a way that I can’t be as good as I need to be without Lee [Newcomer]. And if you think about the ecosystem of healthcare, especially led by oncology, we need that transformation in the ecosystem. We don’t even have the right with regard to regulation. We’re still struggling with how you can put a diagnostic and a therapeutic together into an interoperable system, let alone a much more complex product coming out of regenerative medicine.”

When thinking about a sports metaphor to describe the upcoming proceedings of the American Association of Cancer Research (April 6-10, Washington DC), we were reminded of football. No, not the European (and some would say, proper) kind, but American football. At this time of the year, aspiring college players undertake a week-long ritual known as the NFL Combine. Players assemble in Indianapolis (!) are a put through a grueling schedule of sprints, feats of strength, and agility tests that are specific to the position the player hopes to fill. Some of these are more preposterous than others, and seem to have been conceived by deranged reality TV script writers (is that redundant?). Based on their performance in such events as the 40-yard dash and bench press, their prospects may raise or fall for the NFL Draft in April.

Putting Novel Compounds Through Their Paces

So our thoughts turned to AACR and the similarities with the Combine; a parade of antibodies, small molecules, antisense oligos, siRNA constructs, vaccines, etc. The AACR is traditionally the proving ground for those agents that someday hope to make it to the plenary at ASCO; sticking with the football metaphor, this is like getting to the Super Bowl of oncology (or at least analogous to the conference championship). While the proceedings of AACR are rarely immediately impactful, many of the stars of today, such as ibrutinib, idelalisib, ipilimumab, vemurafenib, and palbociclib, were once nothing more than a poster presentation at AACR. While there are also many false positives that evidence themselves here, the prospecting can be very lucrative to the trained eye. In today’s favorable environment towards oncology, timelines can become highly compressed (INFI being one of the best examples of this) between the time a compound shows activity in the lab to the time clinical responses are being seen in patients.

Many of AACR 2012’s themes will repeat themselves at AACR 2013

A scan of the titles of the topical discussions and abstract titles suggests that many of the themes that played out last year will once again take the spotlight in 2013. One of our favorite topics is that of epigenetics, an area of near total “white space” in oncology research. An educational session on Saturday the 6th will feature topics germane to the entire space. In addition, the plenary session on Monday the 8th will be chaired by Robert Copeland, the CSO of Epizyme, one of the more successful development-stage companies in the space which is concentrating its firepower on histone methyltransferases (HMTs). Also featured will be a number of talks on histone deacetylase inhibitors (HDACs), an area that has yet to fulfill its true promise despite the approval of such agents as Zolinza and Istodax. We also will keep our eyes on further data to be presented by Astex (ASTX), which will provide an update on the clinical activity of SGI-110, a dinucleotide analog of decitabine (Dacogen) in patients with MDS and AML. While something of a new twist on an “old school” hypomethylating agent (HMA), SGI-110 appears to possess intriguing activity in these common conditions, and has show activity in patients who have been pre-treated with first-generation HMAs, Dacogen and Vidaza (azacitidine). Given the relationship to the essentiality of the cancer cell, the epigenetics space has the potential to be as large as or larger than that of kinase inhibitors.

Also big this year will be such topics as tumor cell metabolism, the molecular basis of the cancer stem cell and the EMT, the junction between “steminess” and the epithelium. Expect to hear more about targets such as FAK, Wnt, Notch 1/2 and hedgehog (this story still has more to go beyond Erivedge, in our view). Of course, AACR 2013 will contain the usual panoply of kinase inhibitors. Naturally, with the success of such compounds as idelalisib and IPI-145, a large number of putative contenders to greatness will show their stuff, ranging from the pan-PI3 kinase inhibitors, to combination PI3K/mTOR inhibitors, AKT/mTOR inhibitors, and MEK inhibitors. It truly is anyone’s guess a priori which amongst these will ultimately be successful, and human clinical data will ultimately sort the winners from the also-rans.

What the “eff” with FGF and IGF inhibitors?

While the F “Family”, namely VEGF and EGF, have yielded successful commercial products (though not always in line with early biologic hypotheses), the same cannot be said of the other members of the growth factor family, namely FGF (fibroblast growth factor) an IGF (insulin-like growth factor). We would throw PDGF (platelet-derived growth factor) onto that pile as well. Despite early expectations of clinical success with inhibitors of these factors, whether they be small molecule or large, receptor or ligand, positive clinical results have been fleeting. Perhaps this is because of the nature of the underlying biology whereby they play more of an accessory, rather than principal, role. In addition, the level of driver mutations and/or overexpression does not seem to have tracked that of VEGF and EGF. Despite the disappointment to date, this may be the year in which FGF (in its various forms) finally emerges as a validated drug target. Several presentations will speak to the biologic validity of the members of the FGF family. Taking them in numerical order, FGFR1 appears to play a key role in a variety of squamous cancer subtypes like SCLC, while FGFR2 may participate in the pathogenesis of breast, prostate and papillary renal cancer. FGF2 also is the subject of a presentation tying its role to the development of resistance to ABL kinase inhibitors in CML (good for Iclusig?). Finally, the link between mutations in FGFR3 and bladder cancer is once again discussed in a paper that describes the activation of FGFR3 to a genomic fusion product. Obviously, wherever a potential target exists, chemical matter will emerge to interact with it. Of interest to us will be a human antibody to FGFR2 IIIc from a company called Attogen Bio, as well as a handful of specific and less-specific (a/k/a “dirty”) kinase inhibitors such as AZD4547 and PD173074 in the former category, and dovitinib (can you believe it’s still alive?) and ponatinib (Iclusig). Definitely a space to watch, in our view. Happy prospecting!

Fabrice André, MD, PhD, has focused his research on translational oncology and the development of novel targeted agents for the treatment of breast cancer through his research as an associate professor and director of INSERM Unit U981 at the Institut Gustave-Roussy in Villejuif, France.

He is one of the principal investigators of a prospective clinical trial, SAFIR01, in France that is combining genomic sequencing and tumor biopsy data for better treatment decision making in women with metastatic disease.

André will discuss the need to individualize treatment for patients based on their tumor biology in his presentation, “Use of Genomic Approaches to Select Patients for Targeted Therapy,” scheduled for Friday at 8:15 AM. In this interview, André addresses several targets being explored in clinical research.

Currently, patients with HER2-positive breast cancer are treated with adjuvant trastuzumab-based therapy, and those with estrogen receptor (ER)-positive disease are treated with hormonal adjuvant therapies. For other types of breast cancer, what are the selective targeted therapies that appear promising and how far away are they from widespread use?

Are there any trials that have been completed or are ongoing that you would highlight?

André: CDK4 inhibitors were highly effective in a phase II trial reported at the San Antonio Breast Cancer Symposium in 2012 [Abstract S1-6]. The CDK4/6 inhibitor, PD 0332991, in combination with letrozole, showed a significant improvement in progression-free survival, an 18.6 month difference, compared with letrozole alone. The study was in postmenopausal women with ER-positive, HER2-negative advanced breast cancer.

The mTOR inhibitor everolimus is a first-in-class drug approved for women with advanced ER-positive breast cancer based on the BOLERO-II trial. What kind of impact has this targeted therapy had on treating these patients?

André: Everolimus is improving outcomes for these ER-positive patients. But on top of that, these results open other avenues. Now we can further develop trials and drugs to fine-tune this first-in-class result.

There are at least two trials, in the US and in France, that are addressing the utility of everolimus in the adjuvant setting. Can you discuss the designs of these trials?

André: Yes, one trial by SWOG (Southwest Oncology Group), one of the five cooperative groups that are part of the National Cancer Institute’s network of clinical trials, compares endocrine therapy to endocrine therapy plus everolimus 10 mg per day for one year, right after chemotherapy (ClinicalTrials.gov Identifier: NCT01674140). The French trial will compare endocrine therapy with or without everolimus for two years in patients who are free of disease after three years of endocrine therapy. The French trial will recruit patients with more than three positive nodes after neoadjuvant therapy. In the US trial, the patients need to be at high risk for recurrence, with one to three positive nodes, or else have four or more positive nodes independent of their recurrence score.

Aromatase inhibitors are widely used as treatment for postmenopausal women who have hormone receptor positive-disease, but not all patients respond and even those who do will still inevitably stop responding. Are we any closer to understanding the mechanisms of either primary resistance or acquired resistance to aromatase inhibitors?

André: The mechanisms of resistance to aromatase inhibitors are multiple and may involve kinase activation either at baseline or after treatment exposure. A trial in France that is starting soon will perform biopsies and also high-throughput genomic analyses in patients who present resistance to aromatase inhibitors.

What has been the progress in identifying molecular markers, either alone or in conjunction with biological features, which render a patient unresponsive to chemotherapy? What are the main challenges of understanding the pathways of inherent or acquired chemotherapy resistance?

André: Chemotherapy is more complex than endocrine therapy, since it can have many mechanisms of action. We are still struggling to find molecular mechanisms of chemoresistance. Nevertheless, it seems that immune activation could play a role in the sensitivity to chemotherapy.

There have been many attempts to characterize triple-negative breast cancer and identify novel subtypes. What have been the main challenges in identifying these subtypes?

André: Triple-negative breast cancers account for around 15% of all breast cancers. So, the number of samples we can obtain from triple-negative patients is lower than that for ER-positive subtypes, so the research moves slower. Triple-negative breast cancer is a highly unstable disease at the genomic level. This means that a patient’s disease can look different over time due to genomic instability. Nevertheless, several papers have recently succeeded in proposing homogenous subclasses of triple-negative breast cancers. This new research suggests that triple-negative breast cancers include tumors with mutations in DNA repair, with immune activation, and activation in the Src tyroskine kinase and in the PI3K pathway.

What is a current, interesting target or class of targets for triple-negative breast cancer?

André:The most promising target is certainly the Chk1 protein in this field.

The Overdiagnosis and Overtreatment of DCIS
By Ben Leach

According to the American Cancer Society, more than 60,000 cases of ductal carcinoma in situ (DCIS)—a noninvasive form of breast cancer in the lining of the milk ducts—are diagnosed and removed each year in the United States. However, despite treatment, a concomitant decrease in the incidence of invasive breast cancer has not been observed.

The logical conclusion, according to Laura J. Esserman, MD, MBA, director of the Carol Franc Buck Breast Care Center and co-leader of the Breast Oncology Program at UCSF Helen Diller Family Comprehensive Cancer Center in San Francisco, California, is that DCIS is being overdiagnosed and overtreated.

“I think it’s important because it’s not clear that DCIS is indeed the precursor of cancer,” Esserman said in an interview. “It’s simply a risk factor for invasive cancer, and we need to get our treatment of this entity in line with the way we treat other risk factors for breast cancer.”

Esserman will give her thoughts on some of the shifts that she feels are required to adequately treat DCIS in a presentation on Friday at 9:30 AM entitled, “Are We Overdiagnosing and Overtreating DCIS?”

One of the key shifts Esserman said is needed to treat DCIS appropriately is to recognize the difference between larger, potentially invasive lesions and smaller lesions that have a very low potential to become malignant.

“I think we need to distinguish that DCIS is not one entity just like breast cancer is not one entity,” Esserman said. “A lot of these small, low-grade lesions are clearly no different from atypia, and they should be treated as such.”

Screening studies that are used to identify these indolent lesions bring them to clinical attention, and therefore, lead to the potential for overdiagnosis. Esserman said that the Oncotype DX test for DCIS has consistently found that the risk of developing invasive cancer ranges from 2.5% to 10% at 5 years, and perhaps as high as 20% at 10 years.

“That [level of risk] is really not a whole lot different from someone walking around the street,” Esserman said. “In many cases, we’re treating non-disease. We treat mutation carriers who have an 85% risk of developing cancer quite differently. We don’t operate on them all. We offer prophylactic surgery as an option to some patients, but only when it’s appropriate.”

To lower the rate of overdiagnosis, Esserman said that oncologists should adopt strategies designed to minimize the detection of these inconsequential or minimal risk lesions. Even though the Oncotype DX DCIS test is relatively accurate, other methods may be required to determine if women who are diagnosed with DCIS are truly at risk for developing invasive disease.

Esserman said a better classification system would allow oncologists to change the terminology associated with DCIS, including removal of the term cancer for patients with low-risk lesions.

“It is not a cancer,” Esserman said. “It is a risk factor for developing invasive disease. That’s how it should be presented. People should be presented the risks and the actions for close surveillance, prevention, and treatment.”

Esserman said that the University of California campuses have collaborated on establishing a registry for DCIS to help determine what the best approach is to reclassifying DCIS. However, she said that it would take several such registries across the United States working collaboratively to enable groups like the American Society of Clinical Oncology and the National Comprehensive Cancer Network to recommend sweeping changes in how DCIS is classified.

“I think that Barry Kramer, MD, MPH, who is head of the Division of Cancer Prevention at the National Cancer Institute, considers this to be a top issue,” Esserman said. “He actually agrees that overdiagnosis and overtreatment is common and prevalent, and we actually are recommending a change in the classification of these lesions. We’ve called for efforts to change the threshold for biopsy and to use time to enable us to really learn to not make people feel that they need an intervention, but that they need to be watched closely so we can start to learn a lot more about it.”

While Esserman said these changes are necessary, she also said that many clinicians have embraced the idea that some lesions pose more of a risk than others, and that these patients should receive different treatment options for their disease. Rather than intervention, Esserman said prevention strategies should instead be emphasized to women who have these indolent lesions.

“We need to focus on improving treatments for the people who are at risk to die of their disease and reducing therapeutic interventions for people who don’t have risky disease and the treatments will make them worse than what they have,” Esserman said. “We need to restrict our interventions to people who have extensive high-grade DCIS, and to start offering different options to the rest.”

Although multigene signature tests are being widely used in the United States to help oncologists evaluate the need for adjuvant chemotherapy for certain patient populations, two large clinical trials are expected to define the impact that employing genomic tests in treatment decisions has on survival outcomes, according to Martine J. Piccart, MD, PhD.

Piccart, director of Medicine at the Jules Bordet Institute in Brussels, Belgium, discussed genomic testing and its translational value thus far during a presentation and subsequent interview Friday morning at MBCC.

As president of the European Society of Medical Oncology, Piccart recently cautioned that the era of personalized medicine has not truly arrived, and she echoed that theme in her remarks at the conference.

She said that although “we have witnessed the development of several quite good multigene prognostic signatures,” not much progress has been made in terms of predictive tools that help clinicians select the best chemotherapy.

“We’ve come to realize that identifying predictive markers is really a very complex endeavor,” Piccart said. “One of the reasons that we have probably failed up until now is that we have concentrated our efforts on the tumor and it’s becoming increasingly [apparent] that the macroenvironment plays a major role.”

In less than a decade, prognostic genomic testing has become widespread in the United States, but less so in Europe, Piccart noted. “Information generated from genomic tests has resulted in a change in decision making in approximately 25% to 30% of cases,” according to the IMPAKT 2012 Working Group, a cooperative translational research effort in Europe that Piccart helped develop.1

The researchers concluded that OncotypeDX, a 21-gene recurrence score, and MammaPrint, a 70-gene assay, have demonstrated analytical and clinical validity.

OncotypeDX has been incorporated into the American Society of Clinical Oncology and National Comprehensive Cancer Network guidelines; it is indicated for women with stage I/II, node-negative, estrogen receptor-positive invasive breast cancer who will be treated with hormone therapy and provides a score for the risk of local recurrence.

The IMPAKT group said there are not enough available data to arrive at a conclusion on the analytic and clinical validity of four other tests: CGI, a 97-gene assay; PAM50, a 50-gene assay; the Breast Cancer Index, a 2-gene ratio and molecular grade index; and EndoPredict, an 11-gene assay.

Piccart said EndoPredict has been gaining popularity in Europe. She said that EndoPredict incorporates information on Ki67, a nuclear antigen used to compare proliferation between tumor samples2, and on tumor burden to predict for long-term disease-free survival.

So far, the genomic tests have aided in treatment decisions, Piccart said. She said the tests are useful for luminal breast cancers, not for HER2-positive or triple-negative malignancies that would automatically be classified as high risk.

“These tests are already now quite useful in the clinic and have already led to a significant decrease in adjuvant chemotherapy prescription in the United States,” Piccart said in an interview.

“We are still waiting for the results of these very important trials, TAILORx and MINDACT, to be completely sure that these tests are clinically useful and improve the outcome of patients,” she said. “In this case, what we expect is a reduction in chemotherapy prescriptions without any worsening of survival.”

Oncology Enters Era of GenomicsSledge Calls for Overhaul of Clinical Trials System
By Anita T. Shaffer

As the genomic era in oncology unfolds, the development of new therapeutics increasingly will involve targeting a range of mutations simultaneously, requiring a “next-generation clinical trials system” to match the advances that technology is delivering, according to George W. Sledge, Jr, MD.

Sledge told attendees at the 30th Annual Miami Breast Cancer Conference Saturday that last year marked a leap forward in understanding breast cancer as the results of many genomic analyses became available. The range of mutations uncovered in individual tumors will necessitate moving beyond battling cancer by identifying a particular molecular process, as has been the case in the targeted therapy era, to multiple driver mutations.

“We’re clearly entering a new age and that age is what I consider to be the genomic era,” said Sledge, who is chief of the Oncology Division at Stanford University School of Medicine in California and a past president of the American Society of Clinical Oncology. “This is an era of great promise. We’re at the point where we’ll be able to tell an individual what’s driving their cancer but it’s going to require a whole lot more of us.”

In developing new therapeutics, researchers will have to focus not only on qualitative mutations but also quantitative aberrations, Sledge said. “We don’t need a magic bullet, we need a magic shotgun,” he said. “We need something that can shoot pellets at a lot of different targets and do so more or less simultaneously.”

He said the current clinical trials system is poorly equipped to take advantage of advances in knowledge about cancer genomics and that many changes are needed. His ideas for overhauling the system include trials designed around multitargeting, greater collaboration among research entities, an information network for clinical trials, a redesigned informed consent process, and a “fundamentally different regulatory apparatus.”

Sledge noted that technological advances have delivered an explosion of information at an ever-decreasing cost. He said the sequencing of the first human genome took 13 years and cost approximately $3 billion; in the next several years, researchers likely will be able to sequence a genome in less than two weeks at a cost of about $1000. He said the price would drop further and that the challenge would be using the information generated.

“The evaluation of that gene chip that you order will be incredibly complicated and will require a significant amount of playing out over the next decade in terms of how we use it,” he said.

Sledge said genomics research has revealed that cancers can be described broadly as either “stupid” or “smart.”

Cancers that are stupid have a single dominant mutation and a small mutational load, meaning that monotherapy will be effective and that resistance to therapy will occur rarely and along the same pathway.

In contrast, smart cancers show multiple mutational drivers with a large mutational load, requiring multitargeted therapy to which resistance is common and occurs early in treatment.

Chronic myeloid leukemia, with bcr-abl as a target and a relatively small mutational load, is an example of a stupid cancer, Sledge said. Smart cancers with a greater mutational load include those where patients’ lifestyles play a role, such as lung cancer and melanoma.

Breast cancer falls in the middle of the mutational spectrum, with subtypes that reflect the genomic complexities of the malignancies, Sledge said. “This distinction between stupid cancers and smart cancers drives a lot of what we know about the prognosis of human cancers, and it increasingly will drive how we approach these cancers from a therapeutic standpoint,” he said.

For example, Sledge said, an analysis of triple-negative breast cancer found 32 somatic mutations,1 showing a “genomic chaos” that makes the malignancy a collection of orphan diseases. Attacking a tumor type with so many mutations becomes an oncology version of the Whack-a-Mole arcade game, he said.

“We’re dealing with this rapid emergence of compensatory mechanisms of resistance that have a deep genomic basis which we now for the very first time in human history can measure and increasingly will be able to measure by an individual basis,” Sledge said. “One has to think this will change how we think about the cancer and how we approach cancer from a therapeutic standpoint.”